ABSTRACT Understanding the transcriptional programs that define cell type and regulate the inflammatory responses in macrophages and vascular endothelium is of central interest in understanding/preventing prevalent cardiovascular diseases. The molecular strategies that dictate these critical transcriptional programs reflect, in large part, the actions of dedicated repression checkpoints and the functions of enhancers that modulate cell type-specific gene expression programs. How the programs dictated by an enhancer code underlying such programs remains a fundamental question in regulatory and cardiovascular biology. Our studies under this Grant have linked integration of inflammatory and anti-inflammatory signaling pathways and inhibiting atherosclerosis, uncovering functionally-distinct pathways utilized by PPAR and LXRs, and provided initial insights into the large programs of transrepression critical for blocking inflammatory pathways. Here, we will use genetic and epigenetic approaches to uncover the in vivo roles of dedicated enhancer networks in cardiovascular disease. We propose to focus on the molecular determinants of cel type-specific gene enhancer programs and three-dimensional genomic interaction networks that underlie developmental and newly discovered regulatory programs in the cardiovascular system and macrophages. We will link these programs to two important myocardial infarction susceptibility loci, based on results from genome-wide association studies (GWAS), providing an unprecedented opportunity, based on human genetic models, to further define and delineate the role of three-dimensional enhancer networks and epigenetic strategies in development and disease of the cardiovascular system. These studies should provide a general approach to investigating disease susceptibility loci for many classes of disease.